The primary goal of this competing continuation (renewal) proposal is to combine clinical, cognitive and neuroimaging methodologies to continue our investigations of how estrogen and related compounds influence the cognitive functions of the cholinergic systems of the human brain. We will move beyond our original investigations to begin to develop an understanding of the biological, clinical, and cognitive relationships between positive or negative effects of estrogen on cholinergic-related cognitive functioning in older women. There is evidence that the postmenopausal estrogen treatment may slow or prevent cognitive decline, enhance cognitive functioning, and may lower the risk of developing Alzheimer's disease (AD) if administered in the early postmenopausal period. However, large prospective studies such as the Women's Health Initiative (WHI) have suggested that under certain circumstances, hormone therapy may actually increase the risk for cognitive dysfunction. In the first five year period of this grant, we have consistently shown that benefits of estrogen treatment on cognitive functioning may be mediated through interactions with CNS cholinergic systems by specifically enhancing cholinergic-sensitive cognitive operations including attention, psychomotor speed, and episodic memory. This proposal proceeds to the next logical steps to more fully understand the nature of the estrogen-cholinergic interactions and utilize new approaches (e.g. neuroimaging) to develop a better grasp of the relationships between individual biological and cognitive characteristics and the responsiveness of the CNS cholinergic system to E2 stimulation. Specifically, the first study (1) will examine the relationship between the effects of estrogen on cholinergic system-related cognitive performance and individual characteristics of postmenopausal women that may bear a relationship on whether estrogen has cognitively enhancing effects. This study will involve our model of short-term estrogen treatment and cholinergic antagonist challenge in normal postmenopausal women successfully utilized in the prior grant period. We will examine the influence of subjective and objective baseline cognitive symptomatology, structural brain imaging, and genetic markers on the relationship between the ability of estrogen to enhance cholinergic-related cognitive function. In the second study (2), we will examine the relationship between age and potential benefit to cholinergic-related cognitive performance. We will explicitly examine this version of the critical period hypothesis by utilizing our established estrogen- cholinergic challenge model and examining for age-related differences in brain activity with fMRI that are associated with cognitive differences in estrogen-cholinergic responsivity. This continued work will have important implications for understanding of the effects of hormonal loss on brain function and the potential benefits versus risks of postmenopausal hormone therapy on cognition and behavior. PUBLIC HEALTH RELEVANCE: We have established evidence that estradiol administration in normal postmenopausal women specifically enhances cognitive operations that are influenced by central cholinergic systems including attention, psychomotor speed, and episodic memory. This proposal attempts to more fully understand how estrogen-cholinergic interactions in the brain affect attention and memory and develop an understanding of the relationships between individual, chronological, biological, and cognitive characteristics of older women and the responsiveness of the CNS cholinergic system using new technologies (e.g. neuroimaging). The over arching goal is to develop information to allow the development of models to potentially predict which women may benefit from the cognitive effects of estradiol after menopause.